The interplay between BDNF and PGC-1 alpha in maintaining brain health: role of exercise

Abstract

Throughout our evolutionary history, physical activity has played a significant role in shaping our physiology. Advances in exercise science have further reinforced this concept by highlighting how exercise can change gene expression and molecular signaling to achieve various beneficial outcomes. Several studies have shown that exercise can alter neuronal functions to prevent neurodegenerative conditions like Parkinson's and Alzheimer's diseases. However, individual genotypes, phenotypes, and varying exercise protocols hinder the prescription of exercise as standard therapy. Moreover, exercise-induced molecular signaling targets can be double-edged swords, making it difficult to use exercise as the primary candidate for beneficial effects. For example, activating PGC-1 alpha and BDNF through exercise could produce several benefits in maintaining brain health, such as plasticity, neuronal survival, memory formation, cognition, and synaptic transmission. However, higher expression of BDNF might play a negative role in bipolar disorder. Therefore, further understanding of a specific mechanistic approach is required. This review focuses on how exercise-induced activation of these molecules could support brain health and discusses the potential underlying mechanisms of the effect of exercise-induced PGC-1 alpha and BDNF on brain health.

Keywords: BDNF; PGC-1 alpha; brain health; exercise; molecular signaling.

Figure 1

Possible signaling pathways that interfere with BDNF and PGC-1 alpha during exercise: Exercise-induced lactate increases BDNF concentration mediated by Sirt1, PGC-1 alpha, and FNDC5. Exercise-induced beta-hydroxybutyrate decreases HDAC2 and HDAC3 for epigenetic regulation, favoring BDNF levels. CREB activation activates PGC-1 alpha to increase BDNF concentration. Exercise-induced phosphorylation of PLC-γ increases BDNF-induced glutamate release and Ca2+ flux. Exercise-induced phosphorylation of PLC-γ activates CREB through PI3/AKT, Ras/Raf, MEK/MAPK/ERK1/2. CREB can activate PGC-1 alpha to increase BDNF.

Figure 2

Regular physical exercise can increase BDNF levels, which can activate PGC-1 alpha and FNDC5. This can lead to the activation of the mTOR signaling pathway, resulting in an increase in local protein synthesis in the axon body. Additionally, BDNF can induce autophagy, which causes microglial polarization. This helps to remove damaged neurons. However, it is important to note that high-intensity exercise with longer duration can decrease BDNF concentration, as indicated in the graphical representation. On the other hand, acute exercise with high intensity can increase the BDNF level, as shown by the green mark.